(a) Field of the Invention
The invention relates to a means to enhance insulin-dependent glucose uptake. Specifically, the invention concerns compounds that activate the insulin receptor kinase leading to increased glucose uptake. The invention also concerns methods for treating hyperglycemia in humans, and especially methods for treating Type II diabetes.
(b) Description of Related Art
Among the many functions performed by peptide and protein hormones in metabolism is the ability to interact with receptors with high specificity. The insulin receptor is present on virtually all cells and at high concentrations on the cells for the liver, skeletal muscles, and adipose tissue. Stimulation of the insulin receptor with insulin is an essential element in carbohydrate metabolism and storage.
Diabetics either lack sufficient endogenous secretion of the insulin hormone (Type I) or have an insulin receptor-mediated signaling pathway that is resistant to endogenous or exogenous insulin (Type II, or non-insulin-dependent diabetes mellitus (NIDDM)). Type II diabetes is the most common form of diabetes, affecting about 5% of individuals in the industrialized nations. In Type II diabetics, major insulin-responsive tissues such as liver, skeletal muscle and fat exhibit the insulin resistance (Haring and Mehnert, Diabetologia 36:176-182 (1993); Haring et al., Diabetologia, 37 Suppl. 2:S149-54 (1994)). The resistance to insulin in Type II diabetes is complex and likely multifactorial but appears to be caused by an impaired signal from the insulin receptor to the glucose transport system and to glycogen synthase. Impairment of the insulin receptor kinase has been implicated in the pathogenesis of this signaling defect. Insulin resistance is also found in many non-diabetic individuals, and may be an underlying etiologic factor in the development of the disease (Reaven, Diabetes, 37:1595-1607 (1988)).
Considerable information is known concerning the insulin receptor itself The receptor consists of four separate subunits consisting of two identical a and two identical xcex2 chains. The xcex2 subunits contain a tyrosine kinase activity and the ATP binding sites. The insulin receptor is activated by autophosphorylation of key tyrosine residues in its cytoplasmic tyrosine kinase domain. This autophosphorylation is required for subsequent activity of the insulin receptor. The autophosphorylation stabilizes the activated receptor kinase resulting in a phosphorylation cascade involving intracellular signaling proteins.
At present there are limited pharmacologic approaches to treatment of Type II diabetes. Insulin is currently used as a treatment, but is disadvantageous because insulin must be injected. Although several peptide analogs of insulin have been described, none with a molecular weight below about 5000 daltons retains activity. Some peptides which interact with sites on the xcex2-subunit of the insulin receptor have shown enhancement of the activity of insulin on its receptor (Kole et al., J. Biol. Chem., 271:31619-31626 (1996); Kasuya et al., Biochem. Biophys. Res. Commun., 200:777-83 (1994)). Kohanski and others have reported on a variety of polycationic species that generate a basal effect, but do little to enhance insulin action (Kohanski, J. Biol. Chem., 264:20984-91 (1989); Xu et al., Biochemistry 30:11811-19 (1991). These peptides apparently act on the cytoplasmic kinase domain of the insulin receptor.
In addition, certain non-peptide components have been found to enhance the agonist properties of peptide hormones, but none appear to act directly on the insulin receptor kinase. For instance, the ability of thiazolidinediones, such as pioglitazone, to enhance adipocyte differentiation has been described (Kletzien, et al., Mol. Pharmacol., 41:393 (1992)). These thiazolidinediones represent a class of potential anti-diabetic compounds that enhance the response of target tissues to insulin (Kobayashi, Diabetes, 41:476 (1992)). The thiazolidinediones switch on peroxisome proliferator-activated receptor xcex3 (PPARxcex3), the nuclear transcription factor involved in adipocyte differentiation (Kliewer et al., J. Biol. Chem., 270:12953 (1995)) and do not have a direct effect on the insulin receptor kinase. Other anti-diabetic agents currently in use include both insulin secretagogues (such as the sulfonylureas) and biguanides (such as metfornin) that inhibit hepatic glucose output. To date, non-peptide substances which can mimic the activating effect of insulin on the insulin receptor have eluded discovery.
Bisnaphthalene ureas are known to the literature. They are heavily described as polysulfonic acid derivatives of suramin and as azo dyes. A variety of these polyanionic sulfonic acid derivatives have been established as potential therapeutics for a variety of disease indications. Suramin, described in 1917, is a polysulfonic acid that has been extensively researched (Dressel, J. Chem. Ed., 38:585 (1961); Dressel, J. Chem. Ed., 39:320 (1962)). It has therapeutic uses as an anthehnintic and antiprotozoal. More recently, it has been described as an inhibitor to reverse transcriptase in certain avian and murine retroviruses (De Clercq, Cancer Letter, 8:9 (1979); Mitsuya et al., Science, 226:172 (1984); Gagliardi et al., Cancer Chemother. Pharmacol., 41:117 (1988); Doukas et al., Cancer Res. 55:5161 (1995); Mohan et al., Antiviral Chem., 2:215 (1991)). Large numbers of compounds relating to suramin exist. Most of the suramin analogs which have been reported have multiple sulfonic acid functionality on each aryl ring. Recent studies indicate that polyanionic surarnin analogs have anti-angiogenic, antiproliferative activity, and anti-viral activity (Gagliardi et al., Cancer Chemother. Pharmacol., 41:117 (1988); Doukas et al., Cancer Res., 55:5161 (1995); Mohan et al., Antiviral Chem., 2:215 (1991)). A number of bisnaphthylsulfonic acids have been described in the patent literature as complement inhibitors (U.S. Pat. Nos. 4,132,730, 4,129,591, 4,120,891, 4,102,917, 4,051,176). Additionally, there are a number of azo dye patents (DE 19521589, U.S. Pat. No. 3,716,368, DE 2216592, FR 1578556) which disclose polysulfonated naphthalene azo compounds. Bisnaphthalene urea 2-sulfonamide 3-azo compounds have been solely reported as a recording liquid (JP 58191772). However, none of the suramin analogs or azo dyes have been suggested to be useful in the treatment of hyperglycemia or diabetes.
This invention is directed to bisnaphthalene ureas which enhance glucose uptake in mammals, to pharmaceutical compositions thereof, and to methods for enhancing glucose uptake using these compounds.
In a first embodiment, this invention provides compounds of formula I: 
where
R1 and R2 are substituents on the A rings and are, independently, xe2x80x94SO2NR72, xe2x80x94C(O)NR72, NR7SO2R7, xe2x80x94NR7C(O)R7, xe2x80x94SO2OR7, xe2x80x94C(O)OR7, xe2x80x94OSO2R7, or xe2x80x94OC(O)R7,
R3 and R4 are, independently, hydrogen or lower alkyl, or R3 and R4 together are xe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94, or xe2x80x94(CH2)4xe2x80x94, or R3 or R4 may be an electron pair,
R5 and R6 are, independently, hydrogen, alkyl, substituted alkyl, cyano, halo, nitro, xe2x80x94SR8, xe2x80x94C(O)R8, xe2x80x94SO2OR8, xe2x80x94OSO2R8, xe2x80x94SO2NR82, xe2x80x94NR8SO2R8, xe2x80x94OC(O)R8, xe2x80x94C(O)OR8, xe2x80x94C(O)NR82, xe2x80x94NR8C(O)R8, xe2x80x94OR8, or xe2x80x94NR82,
each R7 and R8 is, independently, hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aryl(lower)alkyl, substituted aryl(lower)alkyl, heteroaryl(lower)alkyl, substituted heteroaryl(lower)alkyl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl,
each Y is, independently, a non-interfering substituent which is not linked to the naphthalene ring via an azo or amide linkage,
each x is, independently, 0, 1 or 2, and
linker connects a carbon designated as c to a carbon designated as d, and is 
xe2x80x83where K is O, S, or NR*, and R* is H, cyano, or lower alkyl; or 
xe2x80x83where R* is H or lower alkyl; or 
xe2x80x83where R* is H, cyano, or lower alkyl; 
xe2x80x83where R* is cyano or lower alkyl;
and, where, if R1 and R2 are both xe2x80x94SO2OH, then:
(i) no Y is xe2x80x94SO2OH;
(ii) neither R5 nor R6 is xe2x80x94SO2OR8 or xe2x80x94OSO2R8; and
(iii) R5 and R6 are not both selected from the group consisting of hydroxy and hydrogen unless at least one (Y)x is (Yxe2x80x2)xxe2x80x2 where xxe2x80x2 is 1 or 2 and Yxe2x80x2is a halo, and the pharmaceutically acceptable salts thereof, as single stereoisomers or mixtures of stereoisomers. These compounds are useful as glucose uptake agonists and in the treatment of hyperglycemia and diabetes.
In a second embodiment, this invention provides pharmaceutical compositions comprising (a) a pharmaceutically acceptable carrier and (b) as an active ingredient, a compound of the first embodiment. These compositions are useful for stimulating the uptake of glucose into cells in a mammal or for treating a mammalian disease state selected from the group consisting of hyperglycemia, type I diabetes, and type II diabetes.
In a third embodiment, this invention provides a method of stimulating the kinase activity of the insulin receptor, comprising contacting the insulin receptor, or the kinase portion thereof, with a compound of the first embodiment, in an amount sufficient to stimulate the kinase activity of the insulin receptor.
In a fourth embodiment, this invention provides a method of activating the insulin receptor is provided, comprising contacting the insulin receptor, or the kinase portion thereof, with a compound of the first embodiment, in an amount sufficient to effect activation of the insulin receptor.
In a fifth embodiment, this invention provides a method for stimulating the uptake of glucose into cells which display the insulin receptor, involving contacting the cells, optionally in the presence of insulin, with a compound of the first embodiment, in an amount sufficient to stimulate the uptake of glucose into the cells. The uptake of glucose into cells in a mammal may be effected by administering the compound of the invention to the mammal.
In other embodiments, the invention provides methods of treating hyperglycemia, type I diabetes, or type II diabetes in a mammal, such as a human by administering a therapeutically effective amount of a compound of the first embodiment or a composition containing said compound.